CAREER: Post-transcriptional regulation of mRNA stability in Mycobacterium smegmatis

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The goal of this project is to understand how bacteria adapt to stressful conditions, such as lack of nutrients or oxygen. Bacteria are known to be able to modify their physiology in order to survive in under adverse conditions, but exactly how this occurs is not well-understood. This work will explore how bacteria activate certain genes and stop using others in order to conserve energy in response to stress. Because bacteria affect human lives in many ways--by shaping our environment, influencing our health, and serving as important tools for research and industry--the results of this study should have far-reaching scientific impacts. In addition, this project will provide valuable training opportunities for graduate and undergraduate students, who will participate directly in the research in both laboratory and course-based settings. Educational impact will be broadened by developing tools and techniques as a platform for involving local high school students and their teachers in hands-on research in the lab and in computational analyses of research results. An educational module for teaching gene regulation will be developed and disseminated to high schools that serve underprivileged communities. Regulation of transcript abundance is critical to bacterial stress response, and can occur at the point of transcription or at the point of degradation. The contribution of post-transcriptional regulation of mRNA stability and function is poorly understood, particularly in mycobacteria, which differ from more commonly studied bacteria with respect to RNA metabolism. Using Mycobacterium smegmatis as a model organism, the objectives of this project are to (i) determine the impact of post-transcriptional regulation on transcript abundance and function in response to stress; (ii) identify mechanisms that globally stabilize mRNA during stress-induced growth inhibition; and (iii) define the roles and regulation of some of the central components of the mycobacterial mRNA degradation machinery. The approach will combine transcriptomics, genetics, biochemistry, and modeling to measure mRNA cleavage and degradation and test hypotheses about the regulation and phenotypic consequences of these processes. This work will generate foundational knowledge about the determinants of mRNA stability in mycobacteria and the contributions of post-transcriptional regulation to stress response. In the longer term, integration of information on transcriptional and post-transcriptional mechanisms is expected to lead to a comprehensive understanding of the stress tolerance mechanisms that render mycobacteria so successful in diverse environments.